There are at least 500,000 victims of cardiac arrest each year in the United States. In the majority of these patients, the initial rhythm is not ventricular fibrillation (VF) or ventricular tachycardia (VT), but is pulseless electrical activity (PEA) or asystole. The survival rates for VT/VF arrests average around 20%. The survival rates for PEA and asystolic arrests are much lower, however, and average only around 5%. There is a critical need, therefore, for improved resuscitation strategies, since each 1% increase in survival rate would result in approximately 5000 additional survivors. This critical need is most apparent with PEA arrests, since little is known about the pathophysiology or the optimal treatment of these arrests, especially when compared to VT/VF arrests. Defibrillation is the definitive treatment for VT/VF arrest, but is not indicated in PEA arrest. We present the novel hypothesis that most PEA arrests are due to failure of ventricular muscle from acute ischemia and/or hypoxia in a substrate where there has been chronic ischemia and/or hypoxia. This contrasts with most VT/VF arrests where acute ischemia causes VT/VF in a healthier substrate. We further hypothesize that this chronic ischemia and/or hypoxia induces preconditioning, which prevents or delays the occurrence of VF, resulting in PEA arrest. We hypothesize, therefore, that therapy for PEA arrests must be directed at reversing this profound ischemia and/or hypoxia, as well as mitigating reperfusion injury. Even though there may be preconditioning, such preconditioning may not be uniform. In addition, the already severe compromise of the metabolic status of the heart would make any degree of reperfusion injury more detrimental in PEA arrests than in VT/VF arrests. Therapy should, therefore, be directed at generating substantial blood flow during resuscitation, including the use of vasodilators, to reverse the profound ischemia that may be present. Methods for augmenting blood flow should include the use of improved external compression devices, which may be particularly useful for treating out-of-hospital arrests; and the use of extracorporeal systems, which may be particularly useful for in-hospital arrests. Controlled reperfusion, including post conditioning, may be necessary at the beginning of reperfusion to reduce reperfusion injury. Additional preservation strategies may also be useful, including intra-arrest hypothermia. Finally, we hypothesize that each of these strategies will have incremental and additive improvement in outcomes from PEA cardiac arrest. The goals of this project are to improve our understanding of the pathophysiology of PEA cardiac arrest, develop improved methods for augmenting blood flow during resuscitation, and also develop synergistic, improved strategies for mitigating the effects of the profound ischemia and/or hypoxia present in PEA arrest. These studies should provide new information and insights about the pathophysiology of PEA cardiac arrests, and may lead to substantial improvements in the now dismal outcomes from PEA cardiac arrests.